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  • Conference paper
    Walker R, Madej B, Lin C, Dickson C, Skjevik A, Yang L, Gould Iet al., 2016,

    Adventures in the world of lipids: Towards the routine simulation of complex membranes and membrane bound proteins

    , Publisher: AMER CHEMICAL SOC, ISSN: 0065-7727
  • Journal article
    Machta BB, Gray E, Nouri M, McCarthy NLC, Gray EM, Miller AL, Brooks NJ, Veatch SLet al., 2016,

    Conditions that Stabilize Membrane Domains Also Antagonize n-Alcohol Anesthesia

    , Biophysical Journal, Vol: 11, Pages: 537-545, ISSN: 1542-0086

    Diverse molecules induce general anesthesia with potency strongly correlated with both their hydrophobicity and their effects on certain ion channels. We recently observed that several n -alcohol anesthetics inhibit heterogeneity in plasma-membrane-derived vesicles by lowering the critical temperature (Tc) for phase separation. Here, we exploit conditions that stabilize membrane heterogeneity to further test the correlation between the anesthetic potency of n -alcohols and effects on Tc. First, we show that hexadecanol acts oppositely to n -alcohol anesthetics on membrane mixing and antagonizes ethanol-induced anesthesia in a tadpole behavioral assay. Second, we show that two previously described “intoxication reversers” raise Tc and counter ethanol’s effects in vesicles, mimicking the findings of previous electrophysiological and behavioral measurements. Third, we find that elevated hydrostatic pressure, long known to reverse anesthesia, also raises Tc in vesicles with a magnitude that counters the effect of butanol at relevant concentrations and pressures. Taken together, these results demonstrate that ΔTc predicts anesthetic potency for n-alcohols better than hydrophobicity in a range of contexts, supporting a mechanistic role for membrane heterogeneity in general anesthesia.

  • Journal article
    Girvan P, Miyake T, Teng X, Branch T, Ying Let al., 2016,

    Kinetics of the Interactions between Copper and Amyloid-β with FAD Mutations and Phosphorylation at the N-terminus

    , Chembiochem, Vol: 17, Pages: 1732-1737, ISSN: 1439-7633

    Mutations and post-translational modifications of amyloid-β (Aβ) peptide in its N terminus have been shown to increase fibril formation, yet the molecular mechanism is not clear. Here we investigated the kinetics of the interactions of copper with two Aβ peptides containing Familial Alzheimer's disease (FAD) mutations (English (H6R) and Tottori (D7N)), as well as with Aβ peptide phosphorylated at serine 8 (pS8). All three peptides bind to copper with a similar rate as the wild-type (wt). The dissociation rates follow the order pS8>H6R>wt>D7N; the interconversion between the two coordinating species occurs 50 % faster for H6R and pS8, whereas D7N had only a negligible effect. Interestingly, the rate of ternary complex (copper-bridged heterodimer) formation for the modified peptides was significantly faster than that for wt, thus leading us to propose that FAD and sporadic AD might share a kinetic origin for the enhanced oligomerisation of Aβ.

  • Journal article
    Zhao W, Jamshidiha M, Lanyon-Hogg T, Recchi C, Cota E, Tate EWet al., 2016,

    Direct targeting of the Ras GTPase superfamily through structure-based design

    , Current Topics in Medicinal Chemistry, Vol: 16, Pages: 16-29, ISSN: 1873-4294

    The Ras superfamily of small monomeric GTPases includes some of the most prominent cancer targets for which no selective therapeutic agent has yet been successfully developed. The turn of the millennium saw a resurgence of efforts to target these enzymes using new and improved biophysical techniques to overcome the perceived difficulties of insurmountably high affinity for guanosine nucleotides and flat, flexible topology lacking suitable pockets for small molecule inhibitors. Further, recent investigations have begun to probe the dynamic conformational status of GTP-bound Ras, opening up new mechanisms of inhibition. While much of the literature has focused on the oncogenic Ras proteins, particularly K-Ras, these represent only a small minority of therapeutically interesting targets within the superfamily; for example, the Rab GTPases are the largest subfamily of about 70 members, and present an as yet untapped class of potential targets. The present review documents the key methodologies employed to date in structure-guided attempts to drug the Ras GTPases, and forecasts their transferability to other similarly challenging proteins in the superfamily.

  • Journal article
    Kumar S, Lockward N, Ramel M-C, Correia T, Ellis M, Alexandrov Y, Andrews N, Patel R, Bugeon L, Dallman M, Brandner S, Arridge S, Katan M, McGinty J, Frankel P, French PMWet al., 2016,

    Quantitative in vivo optical tomography of cancer progression & vasculature development in adult zebrafish

    , Oncotarget, Vol: 7, Pages: 43939-43948, ISSN: 1949-2553

    We describe a novel approach to study tumour progression and vasculature development in vivo via global 3-D fluorescence imaging of live non-pigmented adult zebrafish utilising angularly multiplexed optical projection tomography with compressive sensing (CS-OPT). This “mesoscopic” imaging method bridges a gap between established ~μm resolution 3-D fluorescence microscopy techniques and ~mm-resolved whole body planar imaging and diffuse tomography. Implementing angular multiplexing with CS-OPT, we demonstrate the in vivo global imaging of an inducible fluorescently labelled genetic model of liver cancer in adult non-pigmented zebrafish that also present fluorescently labelled vasculature. In this disease model, addition of a chemical inducer (doxycycline) drives expression of eGFP tagged oncogenic K-RASV12 in the liver of immune competent animals. We show that our novel in vivo global imaging methodology enables non-invasive quantitative imaging of the development of tumour and vasculature throughout the progression of the disease, which we have validated against established methods of pathology including immunohistochemistry. We have also demonstrated its potential for longitudinal imaging through a study of vascular development in the same zebrafish from early embryo to adulthood. We believe that this instrument, together with its associated analysis and data management tools, constitute a new platform for in vivo cancer studies and drug discovery in zebrafish disease models.

  • Conference paper
    Maioli V, Gorlitz F, Warren S, Kumar S, French PMW, Chennell G, Sardini A, Carling D, Alwes F, Dunsby CWet al., 2016,

    Three-dimensional fluorescence imaging by stage-scanning oblique plane microscopy

    , Conference on Three-Dimensional and Multidimensional Microscopy - Image Acquisition and Processing XXIII, Publisher: SPIE, ISSN: 0277-786X
  • Journal article
    Byrne B, Alguel Y, Scull NJ, Craven G, Armstrong A, Iwata S, Diallinas G, Amillis S, Capaldi S, Cameron AD, Lambrinidis G, Mikros Eet al., 2016,

    Structure of eukaryotic purine/Hþ symporter UapA suggests a role for homodimerization in transport activity

    , Nature Communications, Vol: 7, ISSN: 2041-1723

    The uric acid/xanthine H+ symporter, UapA, is a high-affinity purine transporter from the filamentous fungus Aspergillus nidulans. Here we present the crystal structure of a genetically stabilized version of UapA (UapA-G411VΔ1–11) in complex with xanthine. UapA is formed from two domains, a core domain and a gate domain, similar to the previously solved uracil transporter UraA, which belongs to the same family. The structure shows UapA in an inward-facing conformation with xanthine bound to residues in the core domain. Unlike UraA, which was observed to be a monomer, UapA forms a dimer in the crystals with dimer interactions formed exclusively through the gate domain. Analysis of dominant negative mutants is consistent with dimerization playing a key role in transport. We postulate that UapA uses an elevator transport mechanism likely to be shared with other structurally homologous transporters including anion exchangers and prestin.

  • Journal article
    Miller RM, Poulos AS, Robles ESJ, Brooks NJ, Ces O, Cabral JTet al., 2016,

    Isothermal Crystallization Kinetics of Sodium Dodecyl Sulfate–Water Micellar Solutions

    , Crystal Growth & Design, Vol: 16, Pages: 3379-3388, ISSN: 1528-7505

    The crystallization mechanisms and kinetics of micellar sodium dodecyl sulfate (SDS) solutions in water, under isothermal conditions, were investigated experimentally by a combination of reflection optical microscopy (OM), differential scanning calorimetry (DSC), and attenuated total reflection Fourier transform infrared spectroscopy (ATR-FTIR). The rates of nucleation and growth were estimated from OM and DSC across temperatures ranging from 20 to −6 °C for 20% SDS-H2O, as well as for 10 and 30% SDS-H2O at representative temperatures of 6, 2, and −2 °C. A decrease in temperature increased both nucleation and growth rates, and the combined effect of the two processes on the morphology was quantified via both OM and ATR-FTIR. Needles, corresponding to the hemihydrate polymorph, become the dominant crystal form at ≤ −2 °C, while platelets, the monohydrate, predominate at higher temperatures. Above 8 °C, crystallization was only observed if seeded from crystals generated at lower temperatures. Our results provide quantitative and morphological insight into the crystallization of ubiquitous micellar SDS solutions and its phase stability below room temperature.

  • Journal article
    sherlock B, Yu F, Stone J, Warren S, Paterson C, Neil MAA, French PMW, Dunsby CWet al., 2016,

    Tunable fibre-coupled multiphoton microscopy with a negative curvature fibre

    , Journal of Biophotonics, Vol: 9, Pages: 715-720, ISSN: 1864-0648

    Negative curvature fibre (NCF) guides light in its core by inhibiting the coupling of core andcladding modes. In this work, an NCF was designed and fabricated to transmit ultrashort opticalpulses for multiphoton microscopy with low group velocity dispersion (GVD) at 800 nm. Itsattenuation was measured to be <0.3 dB.m-1over the range 600-850 nm and the GVD was-180±70 fs2.m-1at 800 nm. Using an average fibre output power of ~20 mW and pulserepetition rate of 80 MHz, the NCF enabled pulses with a duration of <200 fs to be transmittedthrough a length of 1.5 m of fibre over a tuning range of 180 nm without the need for dispersioncompensation. In a 4 m fibre, temporal and spectral pulse widths were maintained to within10% of low power values up to the maximum fibre output power achievable with the lasersystem used of 278 mW at 700 nm, 808 mW at 800 nm and 420 mW at 860 nm. When coupledto a multiphoton microscope, it enabled imaging of ex vivo tissue using excitation wavelengthsfrom 740 nm to 860 nm without any need for adjustments to the set-up.

  • Conference paper
    Madej B, Dickson C, Skjevik A, Yang L, Gould I, Walker Ret al., 2016,

    Expansion of the Amber Lipid14 force field: Enabling complex membrane molecular dynamics

    , Publisher: AMER CHEMICAL SOC, ISSN: 0065-7727

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